Millions of people after injury or surgery and those suffering from diseases such as arthritis, cancer, and diabetes are afflicted with pain. Nociception (detection of noxious stimuli or harmful stimuli) provides significant biological objects. In other words, it makes living organisms to prepare for environmental hazards and induce pain sensation, reflex withdrawal, and complicated hyperactive and emotional responses, thereby protecting organisms from further damage. The noxious stimuli are detected by specialized high-threshold primary sensory neurons (nociceptors), in which the nociceptors transmit signals to the spinal cord and then transmit the same to the brain with the purpose of higher-level processing that leads to conscious awareness of sensation, called pain. The functional significance of pain perception is exemplified by individual defects in pain receptor, and no the patients who are inherently insensitive to pain can live past the twenties.
Pain may be divided in view of the occurrence area, cause, nature, and mechanism. For example, nociceptive pain is one classified by pathophysiological mechanism, is caused by tissue damage and tends to increase in proportion to harmful stimuli. Generally, the nociceptive pain is self-controlling type and has defensive biological functions by warning of ongoing tissue damage induced by harmful chemical, thermal, and mechanical stimuli. The nociceptive pain includes, for example, post-operative pain, pain associated with trauma, and pain associated with arthritis. On the other hand, neuropathic pain is one of inappropriate adverse reaction regardless of the degree of noxious stimulation, which is characterized by spontaneous pain, hyper-pain, and allodynia.
Pain may be divided into acute and chronic pain depending on the duration of pain. As a representative chronic pain disease, there are neuropathic pain, complex regional pain syndrome, postherpetic neuralgia, postoperative pain syndrome, and the like. Chronic pain is not merely an extension of the acute pain, and the degree of pain may be in non-proportion to the degree of original injury and be occurred spontaneously without stimulation. It is defined as chronic pain when the duration and severity of the pain are detrimental to the function or life of the patient, or the pain lasts over a period of normal tissue healing, usually over three months. The chronic pain is not a symptom, but a disease. The chronic pain is ruthless and cannot be personally controlled and can last for years and decades after the initial injury. The chronic pain is mainly neuropathic in nature and may include the damage of peripheral or central nervous system.
Among the various kinds of pain, neurogenic pain, neuropathic pain, is one that occurs even when there is no cause of injury or pain seemingly. The neuropathic pain is a general term for pain caused by neuronal damage or nervous system disorders such as nerve compression or nerve trauma caused by cancer, autoimmune disease or infection of herpes zoster. The neuropathic pain is chronic pain with clinical characteristics such as allodynia which responds to pain even by stimulation that does not cause pain in normal state, hyperalgesia which is more sensitive to painful stimuli, and spontaneous burning sensation without stimulation. Unlike beneficial acute pain, such neuropathic pain leads to more pain than the pain of the disease due to deformation of the nervous system that transmits pain.
Traditionally, such neuropathic pain has been thought to be caused by hyperexcitability of sensory neurons caused by degeneration of neurons. The causes of hyperexcitability of such sensory neurons are hypothesized as several causes such as 1) changes in homeostasis of the environment around the cell (extra-neuronal homeostasis) due to injury to neurons, 2) expression of sensory neuronal cell membrane ion channel and alteration of ion channel regulatory protein activity due to damage to neurons, 3) new formation of pain transfer circuit caused by synaptic reorganization, and 4) the hyperexcitation of sensory neurons due to the death of inhibitory interneurons.
It has been reported that 3% of the total population live in neuropathic pain. The most common neuropathic pain is hyperalgesia, hypersensitivity, neuropathy, diabetic neuropathy, neuritis, neuralgia, causalgia, allodynia, postherpetic neuralgia, neuromuscular compression, or the like, and in addition, pain associated with cancer, spinal cord injury, post-stroke pain, HIV-related neuropathy, and phantom limb pain. In the United States, it has been reported that the cost of disability related to neuropathic pain is about $40 billion annually, and it is urgent to develop a therapeutic agent for treating such neuropathic pain.
Currently, substances that reduce neurotic excitability or sensory axon conduction is administered against neuropathic pain. Various drugs are used, including antiepileptics, topical lidocaine, analgesics, non-steroidal anti-inflammatory agents, opiad, and the like. However, there are only few studies on substances that can effectively treat neuropathic pain. Because of differences in efficacy and side effects of drugs, it is challenging to select drugs to treat neuropathic pain, and there is a need for the development of novel therapeutic agents against neuropathic pain.
Meanwhile, Evans blue (EB) is harmless to human body and a blue-colloidal azo dye, which binds to albumin and stays in the blood for a long time. It is easy to measure Evans blue because it is less affected by hemolysis, and thus Evans blue is used to measure circulating blood volume. The role of Evans blue in chronic pain diseases or neuropathic pain has not yet been elucidated, and there is no research thereon.